Uncovering genetic predisposition to early onset dementia in patients with Parkinson’s disease/
Prosjekt
- Prosjektnummer
- 911859
- Ansvarlig person
- Janete Chung
- Institusjon
- Helse Stavanger HF
- Prosjektkategori
- Postdoktorstipend
- Helsekategori
- Neurological
- Forskningsaktivitet
- 4. Detection and Diagnosis
Rapporter
The main purpose of this project is to investigate the effect of genetic variation in the progression of Parkinson’s disease.Cognitive impairment is one of the non-motor symptoms that can affect patients with Parkinson’s disease (PD). It varies from subtle cognitive changes to mild cognitive impairment (MCI) and can progress to dementia (Parkinson’s disease dementia) in which a variety of cognitive deficits substantially affect daily life. The evolution of symptoms remains unclear. Studies suggest that MCI increases the risk of conversion to dementia, however, it is possible that PD-MCI remains stable or convert back to a normal cognitive status. The progression to dementia is not inevitable but develops in about 80% of patients with PD.
Cognitive impairment commonly affects four cognitive domains (executive function, attention, visuospatial function, and processing speed) in Parkinson’s disease. Studies have shown variation in with cognitive domains are affected and in which of them are affected first. Thus, the lack of understanding in the heterogeneity in a progression of the cognitive impairment hinders the development of better therapies or preventive strategies.
In order to investigate the association of genetic heterogeneity of Parkinson’s disease and cognitive impairment within a follow up period of 7 years, exome sequencing has been performed on patients with idiopathic Parkinson’s disease from The ParkWest study. We then evaluated the contribution of genetic factors to the progression of cognitive impairment in Parkinson’s disease. Cognitive assessments were collected over 7 years and analyzed together with the genetic data. The main genes studied in this project were catechol-O-methyltransferase (COMT), microtubule-associated protein tau (MAPT), apoliprotein E (APOE), and brain- derived neurotrophic factor (BDNF).
Advanced statistical analysis was performed in this study to evaluate a new method of score conversion (POMP score) for clinical assessment. We also employed the linear mixed regression analyses to study longitudinal measures (repeated measurements from the same participant) of the cognitive assessment and the association with genetic variants. The combination of cognitive assessment and genetic analysis proved to be a powerful tool to understand the progression of disease in Parkinson’s disease.
Despite the limitations we faced during the project, our findings support other genetic cognitive studies, revealing the importance of certain mutations in the development of cognitive impairment in Parkinson’s disease patients. We also show, for the first time, how age and disease severity at the time of first assessment, can determine how genetic factors influence the prognosis of cognitive impairment in subgroups of Parkinson’s disease patients. A manuscript is under preparation and will be submitted in spring 2019.
The main purpose of this project is to investigate the effect of genetic variation in the progression of Parkinson’s disease.Parkinson’s disease (PD) is mainly regarded as a motor disorder; however, non-motor symptoms are very common and affect daily life independently of motor impairment. One type of non-motor symptoms are cognitive impairments, which occur frequently in PD patients. These impairments mainly involve executive, visuospatial and memory functions, and are associated with specific abnormalities in brain regions, which progressively worsen leading to dementia. The ParkVest study showed that overall, 39.1% of patients with baseline or incident PD-MCI progressed to dementia during the first 5 years of the study period. Early detection of cognitive impairment and identification of individuals at risk of dementia are major challenges.
Inherited genetic heterogeneity has been showed to play an important role in the development of dementia, and a number of common genetic variants have been identified to contribute to cognitive function in PD. These included variants in catechol-O-methyltransferase (COMT), microtubule-associated protein tau (MAPT), and apoliprotein E (APOE). Here we combine cognitive assessment and genotyping in the same individuals to understand the interaction between the genotypes and brain regions involved in the different cognitive domains affected by PD.
To achieve this, association analyses were performed to verify the role of these genetic variants in PD patients with dementia (PDD). Genetic analysis suggested the association of APOE (epilson 4) to PD patients with progressive dementia within 7 years, increasing the risk of PDD 3.2-fold comparing with PD patients without APOE variants. This result supports other PDD studies, where APOE ε4 carrier status appears to be associated with a higher frequency of dementia in other cohorts and is over-represented in meta-analysis study.
Statistical analyses was performed to measure the genotype association in PDD, the rate of progression to dementia and longitudinal association between the genotype and cognitive progression score up to 7 years. We have identified some interesting results, however the study showed some limitations which have been worked on to increase the quality of the analyses: a) Accelerated failure time to make statistical inference more accurate and lead to a proper fitting of the mode (the assumption in cox proportional hazard model was not made), and; b) missing data in patients with dementia status. Based on these findings, we are preparing a manuscript that will be submitted in spring 2018.
This project has any direct involvement with the users. However, the project is part of the ParkVest study, in which users are actively involved with regular meetings with an established group at The Norwegian Centre for Movement Disorders, as well Norwegian Parkinson’s Association.
The main purpose of this project is to investigate the effect of genetic variation in the progression of Parkinson’s disease.Parkinson’s disease (PD) is characterized as a movement disorder, with the cardinal motor features of bradykinesia, rigidity and resting tremor reflecting dysfunction within dopaminergic nigrostriatal circuity. However, non-motor symptoms also constitute a significant part of the symptom burden in PD, and cognitive dysfunction is the most relevant non-motor symptom that affects patients’ quality of life. About 50% of patients develop dementia after 10 years into their illness; however, the patterns of cognitive impairment and their speed of evolution vary varies markedly between individuals. Cognitive deficits in PD are heterogeneous in terms of the domains affected, including executive dysfunction, memory, and visuospatial impairments. Several studies have demonstrated that early dysfunction on neuropsychological tests with a posterior cortical basis predicts more rapid progress to dementia, whilst frontostriatally based executive deficits were not associated with earlier dementia. Moreover, neuroimaging demonstrates that atrophy in posterior cortical regions precedes cognitive decline in longitudinal studies, and this posterior cortical dysfunction can predict dementia. The genetic contribution to PD has been shown to play an important role, and a number of common genetic variants have been identified to contribute to cognitive function in PD.
In this part of the study, we investigated if the most common mutations reported to be associated with progression to dementia in PD are also associated with dementia in the ParkVest cohort. We selected five mutations in four genes: BDNF (rs6265), MAPT (rs1800457), APOE (rs429358 and rs7412) and COMT (rs4680). In order to study the cognitive deficits in PD, and the effect of these mutations in each domain, neuropsychological tests were analysed against mutation status carrier.
So far, we have achieved the following results: a) Basic Association analyze for the five mutations in ParkVest; b) Cox proportional hazard model adjusting for age, gender and education to measure the rate of progression to dementia in mutation carriers, and; c) Repeated-measure regression analysis to assess longitudinal association between genotype and cognitive progression score follow up 7 years. We analyzed five different criteria: 1. Global cognition, 2. Executive function, 3. Learning and memory, 4. Visuospatial, 5. Attention.
The main purpose of this project is to investigate the effect of genetic variation in the progression of Parkinson’s disease.Parkinson’s disease is one of the most common neurodegenerative diseases among the elderly, and is characterized by motor disturbance and nonmotor symptoms, including cognitive impairment that can lead to the development of dementia. Studies suggest that individuals with Parkinson’s disease have a 3-5 times higher risk of developing dementia. The genetic contribution to cognitive impairment in Parkinson’s disease, and whether there are genetic factors that can protect or increase the risk of progression to dementia, remains unclear. Genetic studies and association analysis in other neurodegenerative diseases, such as Alzheimer’s disease, have identified many variants associated with dementia. Taken together these studies support a genetic contribution to cognitive impairment and reveal a list of genes associated with dementia.
In this project, we first investigated the genetic variability in ~ 1000 selected genes related to Parkinson’s disease or cognitive decline, using a Target Exome Sequencing approach. Our goal was to identify particular genetic variants among patients with Parkinson’s disease who developed dementia rapidly after disease onset. With the purpose of increasing the power of our study, we subsequently sequenced in a collaborative effort the whole exome of each patients with Parkinson’s disease. Furthermore, this approach allowed us the possibility to study the contribution of variants to cognitive decline and dementia using an unbiased approach.
So far, we have achieved the following results:
a) For the targeted exome sequencing analysis we have: 1. validated the variants overrepresented in the dementia group by genotyping the whole cohort (384 patients and control subjects); and 2. constructed C. elegans strains harboring variants validated in the whole cohort , to further study the biological effect of these variants in this model organism.
b) For the whole exome sequencing analysis we have: 1. Set up bioinformatics pipelines (including PLINK, PLINKSEQ, EPACT, ANNOVAR) for association analyses; 2. validated the single nucleotide variants and insertions/deletions and annotated the variants in the whole-exome sequencing data from 192 patients, and; 3. Described the variability of the candidate genes involved in dementia in the whole cohort.
Next we will perform association analysis and burden testing for the variants in the candidate genes in respect to decline in cognitive function, and the onset of dementia.
One of the main aims of this project, is to investigate how genetic variation affects the observed differences in disease progression among patients with Parkinson's Disease.Parkinson's disease (PD) is a complex, progressive, neurodegenerative disorder that affects more than 1% of people over 60. While 99.9% of human DNA sequence is identical, variability in our DNA sequence can distinguish among individuals, and a small fraction of these differences can influence disease progression. Long-term observational studies demonstrate that 80% of patients with PD may eventually develop dementia (PDD); however, the progression of the disease varies greatly from one patient to another. One of the critical needs in PD is the development of a practical and accurate prognostic test to enable the early identification of patients at risk of PDD.
In this project we set out to uncover the genetic variability among patients with PD, to identify DNA variations that distinguish between individuals who developed dementia relatively quickly after PD diagnosis, and individuals who remained cognitively normal.
The first step of this project was to sequence ~1000 genes related to Parkinson’s disease or cognitive decline in two groups of patients with PD, one that developed early dementia, and another that remained cognitively normal in the same period after diagnosis. To date we have: 1) captured the DNA regions of the ~1000 candidate genes; 2) sequenced the selected regions using Targeted Exome Sequencing; 3. analysed bioinformatically the sequencing results and identified genetic variants present in individuals of the two groups; 4. identified a set of genetic variants that are overrepresented in individuals with early diagnosis of PDD but absent from cognitively normal individuals, and; 5. selected the most interesting variants for further analysis, focusing on those DNA differences that are most likely to effect protein structure and function. These DNA variations are currently being followed up in larger number of individuals to discover whether there is a statistical association between the frequency of any of these genetic variants and specific patterns of disease progression, with special focus on the rate of development of PDD.
Vitenskapelige artikler
Erga AH, Dalen I, Ushakova A, Chung J, Tzoulis C, Tysnes OB, Alves G, Pedersen KF, Maple-Grødem J
Dopaminergic and Opioid Pathways Associated with Impulse Control Disorders in Parkinson's Disease.
Front Neurol 2018;9():109. Epub 2018 feb 28
PMID: 29541058
Lunde KA, Chung J, Dalen I, Pedersen KF, Linder J, Domellöf ME, Elgh E, Macleod AD, Tzoulis C, Larsen JP, Tysnes OB, Forsgren L, Counsell CE, Alves G, Maple-Grødem J
Association of glucocerebrosidase polymorphisms and mutations with dementia in incident Parkinson's disease.
Alzheimers Dement 2018 Oct;14(10):1293-1301. Epub 2018 mai 21
PMID: 29792872
Maple-Grødem J, Chung J, Lunde KA, Tzoulis C, Tysnes OB, Pedersen KF, Alves G
Alzheimer disease associated variants in SORL1 accelerate dementia development in Parkinson disease.
Neurosci Lett 2018 05 01;674():123-126. Epub 2018 mar 19
PMID: 29567423
Deltagere
- Johannes Lange Prosjektdeltaker
- Anastasia Ushakova Prosjektdeltaker
- Ingvild Dalen Prosjektdeltaker
- Kenn Freddy Pedersen Prosjektdeltaker
- Guido Alves Leder av forskningsgruppe
- Maria Doitsidou Hovedveileder
- Jodi Grødem Hovedveileder
- Janete Chung Postdoktor
- Kristin Aaser Lunde Prosjektdeltaker
- Jan Petter Larsen Prosjektdeltaker
eRapport er utarbeidet av Sølvi Lerfald og Reidar Thorstensen, Regionalt kompetansesenter for klinisk forskning, Helse Vest RHF, og videreutvikles av de fire RHF-ene i fellesskap, med støtte fra Helse Vest IKT
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